Summary and Abstract HCC is one of the most common cancers worldwide, accounting for an estimated 600,000 deaths annually. The incidence of HCC has increased in the United States over the past 25 years and the incidence of and mortality rate for HCC are expected to double over the next 10 to 20 years. The increased incidence rate is exacerbated by high mortality rate of HCC. The overall five-year survival rates of patients with HCC in the United States are around 16%, making HCC the most lethal cancer type after pancreatic cancer. Despite its importance, HCC is understudied compared to other major lethal cancers, and hence, our knowledge of the genetic or epigenetic alterations associated with the initiation, progression, and clinical outcomes of HCC is still fragmentary. Furthermore, there is only a limited arsenal of treatment options for HCC as less than one-third of patients with HCC are eligible for potentially curative treatments such as resection, transplantation, or percutaneous ablation. Sorafenib, a multi-kinase inhibitor with antiangiogenic and anti-proliferative effects, has been shown to improve survival in these patients, and has become the standard of care in advanced HCC. However, unfortunately, benefit of sorafenib treatment appears to be marginal extending only 2.8 months of overall survival and a dismal response rate of only 2%, highlighting the urgent need for new targeted agents or finding new ways to overcome resistant to sorafenib. By analyzing proteomic and genomic data from human HCC, we uncovered three molecularly and clinically distinct proteomic subtype of HCC. Analysis with integrated proteomic data with genomic data further showed that PEA15 is highly amplified in HCC genome and its amplification and expression are significantly associated with poor prognosis. Its amplification is not limited to HCC as amplified in bladder cancer, lung cancer, and breast cancer. We demonstrated that PEA15 is up-regulated in vast majority of HCC cell lines and it is essential for proliferation and survival of HCC cells. We further demonstrated that PEA15 promotes invasion of cancer. Our study also showed HCC cells with high PEA15 expression is accountable for angiogenesis. In proposed study, we aim to (1) determine roles of PEA15 in HCC developments. (2) determine roles of PEA15 in angiogenesis. (3) determine if PEA15 is good therapeutic targets for treatment of HCC. If successful, this will open up new opportunity for development of novel therapeutic approaches for poor prognostic patients with HCC. Furthermore, knowledge obtained from this study can be used in other cancer type (i.e. bladder cancer, lung cancer, and breast cancer) in which PEA15 is highly amplified and associated with survival.